Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]CC)=O.[CH2:11]([NH2:14])[CH2:12][NH2:13]>C1(C)C=CC=CC=1>[NH2:13][CH2:12][CH2:11][NH:14][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: NCCN
Reactant: CCOC(=O)c1cccs1
Solvent: Cc1ccccc1
Product: NCCNC(=O)c1cccs1
Temperature: 97.5 °C

Procedure:
A mixture of ethyl thiophene-2-carboxylate (12.0 g.) and ethylenediamine (15.4 ml.) was heated at 95-100° C. for 48 hours. Excess ethylenediamine was removed under reduced pressure and the residue was dissolved in water (150 ml.). The insoluble material [bis(carboxamide)derivative] was removed by filtration. Evaporation of the filtrate gave a residue which was dissolved in toluene (50 ml.). The mixture was evaporated to give N-(2-aminoethyl)-thiophene-2-carboxamide as an oil (12.0 g.) essentially pure by TLC (Rf 0.90; Si02 : 10% v/v methanol in chloroform as eluant) which was used without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:33][CH:34]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(F)(F)F)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2ccc(C(F)(F)F)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-diethyl-8-(4-trifluoromethylphenyl)-2-naphthalenylethynyl]benzoate (Compound 9) 70.0 mg (0.148 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.3 Hz), 7.80 (2H, d, J=8.1 Hz), 7.61-7.47 (6H, m), 6.97 (2H, s), 6.16 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.6 Hz), 1.30 (6H, s).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28].Cl>ClCCl>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[C:31]=1[NH:39][C:40]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)=[O:41])([CH3:28])[CH3:29]
Reactant: c1ccc(CN[C@H]2CC[C@@H](c3ccccc3)CC2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccccc1)[C@H]1CC[C@@H](c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 400 mg of cis-N-benzyl-N-(4-phenylcyclohexyl)amine in 20 ml of dichloromethane were added 2 ml of pyridine and then a solution of 310 mg of 2,6-diisopropylphenylisocyanate in 5 ml of dichloromethane dropwise. The mixture was stirred at room temperature, poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine and then dried over magnesium sulfate. The solvent was distilled away in vacuo to give crude crystals. The crystals were recrystallized from the mixture of ethyl acetate and hexane to give 460 mg of cis-N-(2,6-diisopropylphenyl)-N'-benzyl-N'-(4-phenylcyclohexyl)urea, melting at 153°-154° C.
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]1[N:6]=[C:7]([CH:10]([CH3:12])[CH3:11])[O:8][CH:9]=1>O1CCOCC1.O>[CH:10]([C:7]1[O:8][CH:9]=[C:5]([CH2:4][NH:2][CH3:1])[N:6]=1)([CH3:12])[CH3:11]
Reactant: CN
Reactant: CC(C)c1nc(CCl)co1
Solvent: O
Solvent: C1COCCO1
Product: CNCc1coc(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
To 40% aqueous methylamine (100 mL) was added dropwise a suspension of 4-chloromethyl-2-isopropyloxazole (4.20 g, 0.0263 mol) in p-dioxane/H2O(1:1 (v/v), 20 mL) over a 25 min period. After stirring for 45 min at ambient temperature, the volume was reduced to ca. 50 mL by rotary evaporation in vacuo, and NaCl was added. The aqueous was extracted with CHCl3 (4×100 mL), and the combined extract was dried over Na2SO4 and concentrated in vacuo. The resulting brown liquid was chromatographed on a 200 g SiO2 flash column with 2% iPrNH2 /CH2Cl2 followed by a gradient of iPrNH2 /MeOH/CH2 Cl2 (0.5:2:97.5, 0.5:4:95.5). Concentration in vacuo of the product-containing fractions afforded the desired compound as a golden oil (2.89 g, 0.0187 mol, 71%): 1H NMR (CDCl3) δ 1.33 (d, J=6.9 Hz, 6H), 2.46 (s, 3H), 2.99-3.14 (m, 1H), 3.64 (s, 2H), 7.42 (s, 1H). Mass spectrum: (M+H)+ =155, (M+NH4)+ =172.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([CH:23]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][NH:32][CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.OC1C2N=NNC=2C=CC=1.CC[N+](CCCN(C)C)=C=N>ClCCl>[CH:35]1([CH:23]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:24]([NH:26][C@H:27]2[C@H:34]3[C@H:30]([CH2:31][N:32]([C:14](=[O:16])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:33]3)[CH2:29][CH2:28]2)=[O:25])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: O=C(N[C@@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC[N+](=C=N)CCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H]2CC[C@@H](NC(=O)C(C3CCCCC3)C3CCCCC3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (72.7 mg, 0.314 mmol), 2,2-dicyclohexyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (95 mg, 0.286 mmol) from Example 74, and hydroxybenzotriazole (48.1 mg, 0.314 mmol) were combined in dichloromethane (10 mL). After 20 minutes, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.056 mL, 0.314 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water. The separated organic layer was reduced in volume, and the crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) and eluted first with 10% to 100% ethyl acetate/hexanes and then with 1-10% methanol (2 N ammonia)/dichloromethane to give tert-butyl(R)-1-((3aS,4R,6aR)-4-(2,2-dicyclohexylacetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.26 (dd, J=7.2, 24.0, 1H), 7.91 (d, J=8.6, 1H), 4.48-4.36 (m, 1H), 4.12-3.96 (m, 1H), 3.87 (dd, J=7.4, 10.3, 1H), 3.70 (ddd, J=8.0, 14.4, 23.7, 1H), 3.40 (dd, J=5.7, 12.3, 1H), 2.77 (s, 1H), 2.58 (d, J=6.1, 1H), 2.08 (s, 1H), 2.01 (dd, J=5.6, 10.4, 2H), 1.96-1.55 (m, 17H), 1.54-1.50 (m, 9H), 1.49-1.37 (m, 2H), 1.19 (qdd, J=12.3, 22.3, 24.7, 11H), 1.00 (t, J=6.6, 3H), 0.88 (d, J=6.6, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][C:17]=1[CH:18]=O.C[O-].[Li+]>CN(C)C=O.O>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][C:17]=1/[CH:18]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 60 %

Procedure:
Ex-48A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A, 0.13 g, 0.64 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 0.15 g, 0.64 mmol) in N,N-dimethylformamide (5 mL) was added lithium methoxide (1.0 M in methanol, 1.6 mL, 1.6 mmol). The solution was allowed to stir at ambient temperature for 13 h and then at 40° C. for 2 h. HPLC indicated no further change of starting materials. The reaction mixture was then diluted with water, acidified to pH 5. The resulting precipitate was collected by filtration, washed with water, dried in vacuo. The crude product was slurried in ethanol overnight. The solid was collected by filtration, washed with ethanol, dried in vacuo to give 4-[3E-(2,4-dimethoxy-5-pyrrolidin-1-ylphenyl)acryloyl]benzenesulfonamide (0.16 g, 59%) as a red solid, m.p. 220–222° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=8.7 Hz, 2H), 8.04 (d, J=16.1 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.64 (d, J=16.1 Hz, 1H), 7.52 (s, 2H), 7.18 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.19–3.17 (m, 4H), 1.84–1.83 (m, 4H). HRMS Calcd for C21H24N2O5S: 416.1408 (M+); Found: 416.1408.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(NC(C)=O)nc1
Reaction time: 3 h

Procedure:
To a suspension of (E)-3-(6-acetylaminopyridin-3-yl)acrylic acid (200 mg) in a mixture of dichloromethane (3 ml) and methanol (3 ml) was added a solution of 10% trimethylsilyldiazomethane (3 ml) at ambient temperature and the mixture was stirred for 3 hours. The reaction mixture was evaporated in vacuo, poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was collected by vacuum filtration and washed with diisopropyl ether to give methyl (E)-3-(6-acetylaminopyridin-3-yl)acrylate (197 mg) as a powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]#[N:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:19][OH:20]>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:19][OH:20])[NH2:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C#N
Reactant: NO
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethylthiophene-2-carbonitrile (0.93 g, 3.3 mmol) that was obtained in Example 10 (10c) and a 40% aqueous solution of hydroxylamine (0.5 mL)). Subsequently, the crude product of the title compound thus obtained was purified by recrystallization from hexane (6:4) to afford the title compound (0.60 g) in a yield of 60% as a white crystalline solid.
Reaction SMILES: B(O[O-])=O.[OH2:5].[Na+].[CH3:7][O:8][C:9](=[O:25])[C:10]1[CH:15]=[C:14]([S:16][CH2:17][CH2:18][CH3:19])[N:13]=[C:12]([NH:20][C@H:21]([CH2:23][CH3:24])[CH3:22])[CH:11]=1>C(O)(=O)C>[CH3:7][O:8][C:9](=[O:25])[C:10]1[CH:15]=[C:14]([S@:16]([CH2:17][CH2:18][CH3:19])=[O:5])[N:13]=[C:12]([NH:20][CH:21]([CH2:23][CH3:24])[CH3:22])[CH:11]=1
Reactant: O
Reactant: CCCSc1cc(C(=O)OC)cc(N[C@@H](C)CC)n1
Agent: O=BO[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC[S@](=O)c1cc(C(=O)OC)cc(NC(C)CC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Add sodium perborate monohydrate (0.133 g, 1.33 mmol) to a cooled solution of (S)-2-sec-butylamino-6-propylsulfanyl-isonicotinic acid methyl ester (0.396 g, 1.40 mmol) in acetic acid (4 mL). Stir at room temperature overnight and concentrate. Dissolve the residue in ethyl acetate and wash the solution with aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound (0.230 g, 55%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:26]12[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=1)NC(=O)O[C:27]2=[O:28].C[N:39]([CH:41]=[O:42])C>>[C:41]([C:36]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:28])(=[O:42])[NH2:39]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN(C)C=O
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2C(N)=O)c1
Yield: 77 %

Procedure:
To a solution of the product of Example 2, Step A (200 mg, 0.66 mmol) in 7 mL of DMF was added NaH (53 mg, 1.23 mmol) and the mixture stirred for a few minutes. Isatoic anhydride (160 mg, 0.99 mmol) was added to the reaction mixture and it was stirred for 16 hours. The solvent was removed in vacuo and the resultant residue was flash column chromatographed with 15% of (10/1) mixture of MeOH/NH4OH in CHCl3 to give titled compound (236 mg, 77%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:12].[CH3:14]N(C(N(C)C)N(C)C)C.Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28].Cl>CN(C=O)C.O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH2:12][CH:14]=[N:25][NH:26][C:27]([NH2:29])=[O:28]
Reactant: Cc1c(N(C)C)cccc1[N+](=O)[O-]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: NNC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cccc([N+](=O)[O-])c1CC=NNC(N)=O
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N,N-dimethyl-2-methyl-3-nitroaniline (5.40 g, 30 mmol) in dry DMF (30 ml) was added tris(dimethylamino)methane (6.54 g, 45 mmol) and the mixture was heated to 115° C. under N2 for 4 h. The progress of the reaction was monitored by TLC [EtOAc-hexanes (1:3)]. The dark red solution was cooled in an ice bath, diluted with DMF (20 ml) and a solution of semicarbazide hydrochloride (3.51 g, 31.5 mmol) and conc. HCl (5.4 ml) in water (50 ml) was added. Stirring was continued for 30 min and the pH was raised to 5.0 and after stirring at 0° C. for 30 min, the pH was further raised to 7.5. The precipitated yellow solid was filtered, washed with ice-cold water and ether and dried under vacuum. Recrystallisation from aq. EtOH afforded 31 as yellow microcrystals (3.93 g, 49%), mp 156-157° C. (Found: C, 49.65; H, 5.70; N. 26.14. C11H15N5O3 requires C, 49.81; H, 5.70; N, 26.39%); νmax (Nujol)/cm−1 3450, 3160, 1720, 1600, 1525, 1350.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:2]3[N:7]=[N:6][C:5]([O:8][C@H:9]4[CH:14]5[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]5)[CH2:10]4)=[CH:4][CH:3]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: Clc1ccc(O[C@@H]2CN3CCC2CC3)nn1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: c1cc2cc(-c3ccc(O[C@@H]4CN5CCC4CC5)nn3)ccc2[nH]1

Procedure:
The product of Example 30A (270 mg, 1.1 mmol) was coupled with 5-indolylboronic acid (215 mg, 1.4 mmol) according to the procedure of Example 20B. The title compound was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, PH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (200 mg, 57%). 1H NMR (300 MHz, MeOH-D4) δ 1.49-1.63 (m, 1H), 1.67-1.92 (m, 2H), 1.99-2.14 (m, 1H), 2.28-2.36 (m, 1H), 2.76-3.04 (m, 5H), 3.48 (ddd, J=14.7, 8.2, 1.9 Hz, 1H), 5.24-5.34 (m, 1H), 6.56 (d, J=4.1 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.73 (dd, J=8.6, 1.9 Hz, 1H), 8.07 (d, J=9.5 Hz, 1H), 8.13 (s, 1H) ppm. MS (DCI/NH3) m/z 321 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18][CH2:19][C:20](=[O:40])[C:21]2[CH:22]=[CH:23][C:24]3[C:33]4[CH:32]=[C:31]5[CH2:34][CH2:35][CH2:36][C:37](=[O:38])[C:30]5=[CH:29][C:28]=4[O:27][CH2:26][C:25]=3[CH:39]=2)=[O:17])[CH2:5]1.[Br-:41].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[C@H:6]([C:16]([O:18][CH2:19][C:20]([C:21]2[CH:22]=[CH:23][C:24]3[C:33]4[CH:32]=[C:31]5[CH2:34][CH2:35][CH:36]([Br:41])[C:37](=[O:38])[C:30]5=[CH:29][C:28]=4[O:27][CH2:26][C:25]=3[CH:39]=2)=[O:40])=[O:17])[CH2:5]1
Reactant: [Br-]
Reactant: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
(2S,4S)-1-tert-Butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.66 g, 13.9 mmol) was dissolved in a solution of DCM (100 mL) and MeOH (40 mL), then treated with pyridinium tribromide (4.90 g, 15.3 mmol). After stirring at RT for 1.75 h, the reaction mixture was diluted with DCM and washed successively with 10% HCl, saturated aqueous NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][Cl:42]>CN(C=O)C.C(OCC)(=O)C>[Cl:42][CH2:41][CH2:40][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:32])[CH:14]=3)[C:19]2=[O:23])=[CH:30][CH:29]=1
Reactant: ClCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(O)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCl)cc3)ccc2c1
Temperature: 50 °C
Reaction time: 40 h

Procedure:
To a solution of the product of step i) (500 mg) in DMF (10 mL) was added potassium carbonate (820 mg) and 1-bromo-2-chloroethane (0.2 mL) and the reaction was heated at 50° C. for 22 hours. Additional 1-bromo-2-chloroethane (0.3 mL) and potassium carbonate (820 mg) were added and heating continued for 40 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and brine, dried over magnesium sulphate and evaporated. The residue was purified (SiO2, ethyl acetate:isohexane (6:4)) to yield the sub-titled compound (280 mg).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O>[N:16]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: COC(=O)c1ccc(F)cc1C(F)(F)F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cncn2)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of methyl 4-fluoro-2-trifluoromethylbenzoate (4.95 g) in N,N-dimethylformamide was added 1,2,4-triazole (2.0 g) and potassium carbonate (4.0 g) at 20° C. and the mixture stirred for 4 hours at 60° C. The mixture was diluted (ether), washed (aqueous citric acid) and dried (magnesium sulfate). The residue was purified by chromatography to give methyl 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoate (5.07 g), NMR 3.98(s,3H),7.94-8.05(2H),8.15(2H),8.71(s,1H).
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH:11](OCC)(OCC)OCC.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH:11]=[C:5]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:10])[C:6]([O:8][CH3:9])=[O:7])=[CH:24][CH:23]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: CCOC(OCC)OCC
Solvent: ClCCl
Product: COC(=O)C(=CNc1ccc(Br)cc1)C(=O)C1CC1
Temperature: 130 °C
Yield: 58 %

Procedure:
A stirred mixture of methyl 3-cyclopropyl-3-oxopropanoate (20 g, 0.141 mol), triethyl orthoformate (28 mL, 0.169 mol), and 4-bromoaniline (24.2 g, 0.141 mol) were heated at 130° C. for 5 h with a Dean Stark trap. After this time the reaction was cooled to room temperature, diluted with methylene chloride and filtered through a pad of silica. The filtrate was concentrated to afford the desired product (26.5 g, 55%) as a yellow solid: ESI MS m/z 324 [C14H14BrNO2+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(OCC(=O)c2ccc(C(C)C)cc2)c1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(-c3ccc(C(C)C)cc3)coc2c1
Temperature: 95 °C
Yield: 100 %

Procedure:
A solution of 1-(4-isopropylphenyl)-2-(3,5-dimethylphenoxy)ethanone obtained in Reference Example 142 (38.1 g, 135 mmol) and Montmorillonite KSF (57.2 g) in toluene (400 mL) was heated at 95° C., and was reacted for 16 hours. The reaction solution was cooled to room temperature, and then Montmorillonite KSF was filtered off. The solution was purified by silica gel column chromatography (ethyl acetate:hexane=1:9), and the solvent was distilled off under reduced pressure to obtain 35.6 g (yield 100%) of the title compound as an oily matter. The oily matter was, if necessary, crystallized with methanol. Melting point: 44-45° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[N:11][C:12]([NH2:13])=[C:7]2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[N:5]1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:13][C:12]1[N:11]=[CH:10][N:9]=[C:8]2[N:4]([CH2:3][CH2:2][NH:1][C:30](=[O:31])[CH2:29][C:27]#[N:28])[N:5]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)[C:7]=12
Reactant: NCCn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC(=O)NCCn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
To a solution of 1-(2-aminoethyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (287 mg, 0.829 mmole), 2-cyanoacetic acid (85 mg, 1.0 mmole) and TEA (0.14 ml, 1.0 mmole) in DMF (10 mL) was added HATU (347 mg, 0.912 mmole). After stirring 3 hr at room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with aq. NaHCO3 and brine, then dried (Na2SO4), filtered and concentrated. The resulting residue was subjected to column chromatography (3% MeOH/DCM) to provide 90 mg (22% yield from step 1) of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-cyanoacetamide.